PDF(Pubmed)
Abstract：
The hepatic deletion of Rbpjκ (RbpjF/F::AlbCre) in the mouse leads to exhibition of the Alagille syndrome phenotype during early postnatal liver development with hyperlipidemia and cholestasis due to attenuated disruption of NOTCH signaling. Given the roles of NRF2 signaling in the regulation of lipid metabolism and bile ductal formation, it was anticipated that these symptoms could be alleviated by enhancing NRF2 signaling in the RbpjF/F::AlbCre mouse by hepatic deletion of Keap1 in compound Keap1F/F::RbpjF/F::AlbCre mice. Unexpectedly, these mice developed higher hepatic and plasma cholesterol levels with more severe cholestatic liver damage during the pre-weaning period than in the RbpjF/F::AlbCre mice. In addition, hypercholesterolemia and hepatic damage were sustained throughout the growth period unlike in the RbpjF/F::AlbCre mouse. These enhanced abnormalities in lipid metabolism appear to be due to NRF2-dependent changes in gene expression related to cholesterol synthetic and subsequent bile acid production pathways. Notably, the hepatic expression of Cyp1A7 and Abcb11 genes involved in bile acid homeostasis was significantly reduced in Keap1F/F::RbpjF/F::AlbCre compared to RbpjF/F::AlbCre mice. The accumulation of liver cholesterol and the weakened capacity for bile excretion during the 3 pre-weaning weeks in the Keap1F/F::RbpjF/F::AlbCre mice may aggravate hepatocellular damage level caused by both excessive cholesterol and residual bile acid toxicity in hepatocytes. These results indicate that a tuned balance of NOTCH and NRF2 signaling is of biological importance for early liver development after birth.
摘要：
小鼠中Rbpjκ（RbpjF/F：：AlbCre）的肝缺失导致出生后早期肝脏发育期间Alagille综合征表型的表现，并伴有高脂血症和胆汁淤积，这是由于NOTCH信号传导的减弱破坏。鉴于NRF2信号在调节脂质代谢和胆管形成中的作用，预期这些症状可以通过在化合物Keap1F/F::RbpjF/F::AlbCre小鼠中通过肝缺失Keap1而增强RbpjF/F::AlbCre小鼠中的NRF2信号传导来缓解。出乎意料的是,与RbpjF/F::AlbCre小鼠相比，这些小鼠在断奶前阶段出现了更高的肝脏和血浆胆固醇水平，胆汁淤积性肝损伤更严重。此外,与RbpjF/F::AlbCre小鼠不同，高胆固醇血症和肝损伤在整个生长期都持续存在。这些增强的脂质代谢异常似乎是由于与胆固醇合成和随后的胆汁酸产生途径相关的基因表达的NRF2依赖性变化。值得注意的是,与RbpjF/F::AlbCre小鼠相比，Keap1F/F::RbpjF/F::AlbCre小鼠中参与胆汁酸稳态的Cyp1A7和Abcb11基因的肝表达显著降低。在Keap1F/F::RbpjF/F::AlbCre小鼠断奶前3周期间，肝脏胆固醇的积累和胆汁排泄能力的减弱可能会加剧由过度胆固醇和肝细胞中残留胆汁酸毒性引起的肝细胞损伤水平。这些结果表明，NOTCH和NRF2信号的调节平衡对于出生后早期肝脏发育具有生物学重要性。
